Non invasive neuromodulation device for enabling recovery of motor, sensory, autonomic, sexual, vasomotor and cognitive function

ABSTRACT

In one example embodiment, a neuromodulation system for inducing locomotor activity in a mammal, in cooperation with a signal generator and an electrode, delivers a signal with an overlapping high frequency pulse to a mammal.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a 371 of PCT/US2012/064874, filed Nov. 13, 2012,which claims benefit under 35 U.S.C. §119(e) from U.S. ProvisionalPatent Application Ser. No. 61/559,025, filed Nov. 11, 2011, thecontents of which are incorporated herein by reference in theirentirety.

BACKGROUND

Serious spinal cord injuries (SCI) affect approximately 1.3 millionpeople in the United States, and roughly 12-15,000 new injuries occureach year. Of these injuries, approximately 50% are complete spinal cordinjuries in which there is essentially total loss of sensory motorfunction below the level of the spinal lesion.

Neuronal networks formed by the interneurons of the spinal cord that arelocated in the cervical and lumbar enlargements, such as the spinalnetworks (SNs), play an important role in the control of posture,locomotion and movements of the upper limbs, breathing, swallowing andspeech. Most researchers believe that all mammals, including humans,have SNs in the lunbosacral cord. See Dimitrijevic, M. R, Gerasimenko,Yu., and Pinter, M. M., Evidence for a Spinal Central Pattern Generatorin Humans, Ann. N. Y. Acad. Sci., 1998, vol. 860, p. 360; Gurfinkel', V.S., Levik, Yu. S., Kazennikov, O. V., and Selionov, V. A., Does thePrime Mover of Stepping Movements Exist in Humans?, Human Physiology,1998, vol. 24, no. 3, p. 42; Gerasimenko, Yu. P., Roy, R. R., andEdgerton, V R., Epidural Stimulation: Comparison of the Spinal CircuitsThat Generate and Control Locomotion in Rats, Cats and Humans, Exp.Neurol., 2008, vol. 209, p. 417. Normally, the activity of SNs isregulated supraspinally and by peripheral sensory input. In the case ofdisorders of the connections between the brain and spinal cord, e.g., asa result of traumatic spinal cord lesions, motor tasks can be enabled byepidural electrical stimulation of the lumbosacral and cervicalsegmentsas well as the brainstem. It has been shown that epidural electricalspinal cord stimulation (eESCS) with enough intensity can induceelectromyographic (EMG) patterns in the leg muscles of patients withclinically complete spinal cord injury. See Dimitrijevic, Gerasimenko,Yu., and Pinter, supra; Minassian, K., Persy, I., Rattay, F, Pinter, M.M., Kern, H., and Dimitrijevic, M. R., Human Lumbar Cord Circuitries CanBe Activated by Extrinsic Tonic Input to Generate Locomotor-LikeActivity, Human 1Hovement Sci., 2007, vol. 26, p. 275. But the noveltyof the approach described in this document is that the spinal circuitrycan be neuromodulated to a physiological state that facilitates orenables the recovery or improved control of movement without actuallyinducing the movement following some neuromotor dysfunction. Harkema,S., Gerasimenko, Y, Hodes, J., Burdick, J., Angeli, e., Chen, Y,Ferreira, e., Willhite, A., Rejc, E., Grossman, R. G., and Edgerton, VR., Epidural Stimulation of the Lumbosacral Spinal Cord EnablesVoluntary Movement, Standing, and Assisted Stepping in a ParaplegicHuman, Lancet, 2011, vol. 377, p. 1938. eESCS is an invasive method andrequires surgical implantation of electrodes on the dorsal surface ofthe spinal cord, which limits this method of activating SNs to clinics.

Recently, noninvasive methods for activating the SNs by means of legmuscle vibration and spinal cord electromagnetic stimulation wassuggested. It was found that the vibration of the tendons of the hipmuscles initiates involuntary walking movements in subjects lying ontheir side with an external support for the legs. See Gurfinkel', V S.,Levik, Yu. S., Kazennikov, O. V, and Selionov, V A., Locomotor-LikeMovements Evoked by Leg Muscle Vibration in Humans, Eur. J lVeurosci.,1998, vol. 10, p. 1608; Selionov, V A., Ivanenko, Yu. P., Solopova, 1A.,and Gurfinkel', V S., Tonic Central and Sensory Stimuli FacilitateInvoluntary Air-Stepping in Humans, J Neurophysiol., 2009, vol. 101, p.2847. In addition, electromagnetic stimulation of the rostral segmentsof the lumbar spinal cord caused involuntary walking movements inhealthy subjects in a similar position with a support for the legs. SeeGerasimenko, Yu., Gorodnichev, R., Machueva, E., Pivovarova, E.,Semenov, D., Savochin, A., Roy, R. R., and Edgerton, V R., Novel andDirect Access to the Human Locomotor Spinal Circuitry, J New'osci.,2010, vol. 30, p. 3700; Gorodnichev, R. M., Machueva, E. M., Pivovarova,E. A., Semenov, D. V, Ivanov, S. M., Savokhin, A. A., Edgerton, V R.,and Gerasimenko, Yu. P., A New Method for the Activation of theLocomotor Circuitry in Humans, Hum. Physiol., 2010, vol. 36, no. 6, p.700. Step-like movements elicited by vibration and electromagneticstimulation, have apparently a different origin. In the former case, theSN is activated by afferent input mainly due to the activation of musclereceptors, whereas in the latter case, the neuronal locomotor network isaffected directly. Each of these methods has its specificity. Forexample, the vibratory muscle stimulation elicits involuntary locomotormovements only in the hip and knee joints, without the involvement ofthe ankle. In addition, these characteristic movements could be evokedonly in 50% of the subjects. See Selionov, Ivanenko, Solopova, andGurfinkel', supra. The percentage of subjects in whom the spinal cordelectromagnetic stimulation evoked involuntary step like movements waseven smaller (10%), although in this case, the kinematic structure ofthe resultant movements was consistent with the natural random step-likemovements to a greater extent than in the case of vibration. SeeGerasimenko, Gorodnichev, Machueva, Pivovarova, Semenov, Savochin, Roy,and Edgerton, supra; Gorodnichev, Machueva, Pivovarova, Semenov, Ivanov,Savokhin, Edgerton, and Gerasimenko, supra. In addition, spinal cordelectromagnetic stimulation is limited by the technical capabilities ofthe stimulator. The modem magnetic stimulator used in clinics (e.g.,Magstim Rapid) can provide only short-exposure stimulating effects. Theelectromagnetic stimulator, with the parameters required to elicitstep-like movements (5 Hz and 1.5 T), could be sustained for only 15 s.

Accordingly, a need exists for the further development ofneuromodulation systems and devices.

SUMMARY

In some embodiments, the neuromodulation system is used with a mammal(e.g., a human) having a spinal cord with at least one selecteddysfunctional spinal circuit or other neurologically derived source ofcontrol of movement in a portion of the subject's body. Transcutaneouselectrical spinal cord stimulation (tESCS) applied in the region of theT11-T12 vertebrae with a frequency of 5-40 Hz may elicite involuntarystep-like movements in healthy subjects with their legs suspended in agravity-neutral position. Amplitude of evoked step-like movements mayincrease with increasing tESCS frequency. Frequency of evoked step-likemovements may not depend on the frequency of tESCS. It was shown thatthe hip, knee, and ankle joints were involved in the evoked movements.In conclusion, transcutaneous electrical spinal cord stimulation (tESCS)can be used as a noninvasive method in rehabilitation of spinalpathology. By way of non-limiting examples, application oftranscutaneous electrical spinal cord stimulation (tESCS) activatesspinal networks (SNs), in part via the dorsal roots and the gray matterof the spinal cord. When activated, the SNs may (a) enable voluntarymovement of muscles involved in at least one of standing, stepping,reaching, grasping, voluntarily changing positions of one or both legs,breathing, swallowing, speech control, voiding the patient's bladder,voiding the patient's bowel, postural activity, and locomotor activity;(b) enable or improve autonomic control of at least one ofcardiovascular function, body temperature, and metabolic processes; (c)help facilitate recovery of at least one of an autonomic function,sexual function, vasomotor function, and cognitive function; and/or (d)help to resolve and/or block pain and spasm.

The paralysis may be a motor complete paralysis or a motor incompleteparalysis. The paralysis may have been caused by a spinal cord injuryclassified as motor complete or motor incomplete. The paralysis may havebeen caused by an ischemic or traumatic brain injury. The paralysis mayhave been caused by an ischemic brain injury that resulted from a strokeor acute trauma. By way of another example, the paralysis may have beencaused by a neurodegenerative brain injury. The neurodegenerative braininjury may be associated with at least one of Parkinson's disease,Huntington's disease, Alzheimer's, dystonia, ischemia, stroke,amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS),and cerebral palsy.

In one example embodiment, a neuromodulation system is configured toapply electrical stimulation to a portion of a spinal cord of thesubject. The electrical stimulation may be applied by at least oneactive of surface electrode that is applied to the skin surface of thesubject. Such an electrode may be positioned at, at least one of athoracic region, a cervical region, a lumbosacral region of the spinalcord and/or the brainstem. Electrical stimulation may be delivered at1-40 Hz at 1-200 mA. The electrical stimulation may include at least oneof tonic stimulation and intermittent stimulation. The electricalstimulation may include simultaneous or sequential stimulation ofdifferent regions of the spinal cord.

In one example embodiment, where the paralysis was caused by a spinalcord injury at a first location along the spinal cord, the electricalstimulation may be applied by an electrode that is on the spinal cord ofthe patient at a second location below the first location along thespinal cord relative to the patient's brain.

In one example embodiment, a method may include administering one ormore neuropharmaceutical agents to the patient. The neuropharmaceuticalagents may include at least one of a serotonergic drug, a dopaminergicdrug, a noradrenergic drug, a GABAergic drug, and glycinergic drugs. Byway of non-limiting examples, the neuropharmaceutical agents may includeat least one of 8-OHDPAT, Way 100.635, Quipazine, Ketanserin, SR 57227A,Ondanesetron, SB 269970, Buspirone, Methoxamine, Prazosin, Clonidine,Yohimbine, SKF-81297, SCH-23390, Quinpirole, and Eticlopride.

The electrical stimulation may be defined by a set of parameter values,and activation of the selected spinal circuit may generate aquantifiable result. In one example embodiment, the neuromodulationsystem is configured to repeat and use electrical stimulation havingdifferent sets of parameter values to obtain quantifiable resultsgenerated by each repetition. Thereafter, a machine learning method maybe executed by at least one computing device. The machine learningmethod builds a model of a relationship between the electricalstimulation applied to the spinal cord and the quantifiable resultsgenerated by activation of the at least one spinal circuit. A new set ofparameters may be selected based on the model. By way of a non-limitingexample, the machine learning method may implement a Gaussian ProcessOptimization.

In one example embodiment, the neuromodulation system is configured toenable at least one function selected from a group consisting ofpostural and/or locomotor activity, voluntary movement of leg position,when not bearing weight, improved ventilation, swallowing, speechcontrol, voluntary voiding of the bladder and/or bowel, return of sexualfunction, autonomic control of cardiovascular function, body temperaturecontrol, and normalized metabolic processes, in a human subject having aneurologically derived paralysis. The method includes stimulating thespinal cord of the subject using a surface electrode and may includesimultaneously subjecting the subject to physical training that exposesthe subject to relevant postural proprioceptive signals, locomotorproprioceptive signals, and supraspinal signals while being stimulatedwith tESCS. At least one of the stimulation and physical trainingmodulates, provokes or incites in real time the electrophysiologicalproperties of spinal circuits in the subject so the spinal circuits areactivated by at least one of supraspinal information and proprioceptiveinformation derived from the region of the subject where the selectedone or more functions are facilitated.

The region where the selected one or more functions are facilitated mayinclude one or more regions of the spinal cord that control: (a) lowerlimbs; (b) upper limbs and brainstem for controlling speech; (c) thesubject's bladder; and/or (d) the subject's bowel and/or other endorgan. The physical training may include standing, stepping, sittingdown, lying down, reaching, grasping, stabilizing sitting posture,stabilizing standing posture, practicing speech, swallowing, chewing,deep breathing and coughing.

The surface electrode may include an array of one or more electrodesstimulated in a monopolar biphasic configuration. Such a surfaceelectrode may be placed over at least one of a lumbar, a lumbosacral orsacral portion of the spinal cord, a thoracic portion of the spinalcord, a cervical portion of the spinal cord and/or the brainstem.

The stimulation may include continuous stimulation and/or intermittentstimulation. The stimulation may include simultaneous or sequentialstimulation of different spinal cord regions. Optionally, thestimulation pattern may be under control of the subject.

The physical training may include inducing a load bearing positionalchange in the region of the subject where locomotor activity is to befacilitated. The load bearing positional change in the subject mayinclude standing, stepping, reaching, and/or grasping. The physicaltraining may include robotically guided training.

The method may also include administering one or moreneuropharmaceuticals. The neuropharmaceuticals may include at least oneof a serotonergic drug, a dopaminergic drug, a noradrenergic drug, aGABAergic drug, and a glycinergic drug.

In one example embodiment, a method includes placing an electrode on thepatient's spinal cord, positioning the patient in a training deviceconfigured to assist with physical training that is configured to induceneurological signals derived from the portion of the patient's bodyhaving motor dysfunction, and applying electrical stimulation to aportion of a spinal cord of the patient.

Another exemplary embodiment is a system that includes a training deviceconfigured to assist with physically training of the patient, a surfaceelectrode array configured to be applied on the patient's spinal cord,and a stimulation generator connected to the electrode. When undertaken,the physical training induces neurological signals derived from theportion of the patient's body having the motor dysfunction. Thestimulation generator is configured to apply electrical stimulation tothe electrode.

Additional features and advantages are described herein, and will beapparent from the following Detailed Description and figures.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a high level block diagram of an example network communicatingsystem, according to an example embodiment of the system disclosedherein.

FIG. 2 is a detailed block diagram showing an example of a computingdevice, according to an example embodiment of the system disclosedherein.

FIG. 3 is a block diagram of an example neuromodulation system inaccordance with one example embodiment of the system disclosed herein.

FIG. 4 is a flowchart illustrating an example procedure for delivering agenerated first signal and a generated second signal.

FIGS. 5A and 5B are diagrammatic views of an example neuromodulationsystem, illustrating an example arrangement or placement of a pluralityof electrodes.

FIG. 6 is a diagrammatic view of alternative arrangements of differenttypes of electrodes.

FIG. 7 is a diagrammatic view of an example signal which is delivered toa mammal.

FIG. 8, panels a and b, show motor responses in the muscles of the rightleg to the tESCS with a frequency of 1 Hz and an amplitude of 75-100 mA(showed at the left of the recordings). The responses in the m. rectusfemoris and m. biceps femoris (RF and BF, respectively), as well as inthe m. tibialis anterior and m. gastrocnemius (TA and MG, respectively)are shown. At the right bottom of the lower recording, there are marksof time in ms, the same for all the muscles, and marks of the amplitudein mV.

FIGS. 9A and 9B show electrical activity of the leg muscles andmovements in the leg joints evoked by tESCS with frequencies of 5 and 30Hz. FIG. 2A: Subject R: the cinematogramms of the joint movements of theright leg and the EMGs of the hip muscles of the right and left legs areshown. Under the EMG, there is a mark of the stimulus. At the right ofthe cinematogram and EMGs, there are vertical marks of the amplitude inangle degrees and mV, respectively. The duration of records is 40 s.FIG. 2B: Subject S: the EMGs of the hip and ankle muscles of the rightleg and the goniograms of the knee joints of the right and left legs;the arrows at the top show the beginning and end of stimulation; thehorizontal and vertical labels next to EMG, 10 s and 0.5 mV,respectively; the vertical mark to the right of the goniograms, 200 m V.H, hip; Kn, knee; Ank, ankle; RF, m. rectus femoris; BF, m. bicepsfemoris; T A, m. tibialis anterior; M G, m. gastrocnemius; (r), on theright; (1), on the left.

FIG. 10 EMGs (left) and trajectories of reflective markers attached tothe right leg; kinematograms (right) recorded during voluntary steppingmovements (vol) and movements caused by tESCS with frequencies of 5 and30 Hz. The duration of records is 10 s. Black and gray lines showmovements in the hip and knee joints, along with calibrations forchanges in joint angles respectively. The remaining designations are thesame as in FIG. 2.

FIG. 11, panels A-E, show interarticular coordination during voluntarystepping movements (vol) and movements caused by tESCS with frequenciesof 5 and 30 Hz. Reconstruction of the movements of the right leg duringone stepping cycle obtained by processing the cinematograms of the(Panel A) forward and (Panel B) backward movements of legs,respectively; the coordination of movements in the (Panel C) hip andknee joints, (Panel D) knee and ankle joints; and (Panel E) thetrajectory of a big toe. Subject R.

FIG. 12, panels a-e, show the average amplitude of movements in the hip(H), knee (Kn), and ankle (Ank) joints caused by tESCS with a frequencyof 5-40 Hz recorded during the first 15 s after the start ofstimulation. The ordinate shows angular degrees. (Panels a, b) SubjectS, different strategies; (Panel b) subject R; (Panel c) subject B;(Panel d) subject E; (Panel e) subject G. Error bars, standarddeviation. Asterisks, significant differences in amplitude recordedduring tESCS with a frequency of 5 Hz, p≦0.05.

DETAILED DESCRIPTION

The present disclosure relates in general to the field of neurologicaltreatment and rehabilitation for injury and disease including traumaticspinal cord injury, non-traumatic spinal cord injury, stroke, movementdisorders, brain injury, and other diseases or injuries that result inparalysis and/or nervous system disorder. Systems and devices areprovided to facilitate recovery of posture, locomotion, and voluntarymovements of the arms, trunk, and legs, and recovery of autonomic,sexual, vasomotor, speech, swallowing, chewing, respiratory andcognitive function, in a human subject having spinal cord injury, braininjury, or any other neurological disorder.

The present system may be readily realized in a network communicationssystem. A high level block diagram of an example network communicationssystem 100 (“system 100”) is illustrated in FIG. 1. In this example,system 100 includes neuromodulation system 102 and informationprocessing system 104.

Information processing system 104 may include a variety of devices, suchas desktop computers which typically include a user display forproviding information to users and various interface elements as will bediscussed in further detail below. Information processing system 104 mayinclude a cellular phone, a personal digital assistant, a laptopcomputer, a tablet computer, or a smart phone. In some exampleembodiments, information processing system 104 may include any mobiledigital device such as Apple Inc.'s iPhone™, iPod Touch™ and iPad™.Further, information processing system 104 may include smart phonesbased on Google Inc.'s Android™, Nokia Corporation's Symbian™ orMicrosoft Corporation's Windows Mobile™ operating systems or Research InMotion Limited's Blackberry™ etc. In these embodiments, informationprocessing system 104 is preferably configured to download, install andexecute various application programs.

Information processing system 104 may communicate with neuromodulationsystem 102 via a connection to one or more communications channels 106such as the Internet or some other data network, including, but notlimited to, any suitable wide area network or local area network. Itshould be appreciated that any of the devices and systems describedherein may be directly connected to each other instead of over anetwork. At least one server 108 may be part of network communicationssystem 100, and may communicate with neuromodulation system 102 andinformation processing system 104.

Information processing system 104 may interact with a large number ofusers at a plurality of different neuromodulation systems 102.Accordingly, information processing system 104 may be a high endcomputer with a large storage capacity, one or more fastmicroprocessors, and one or more high speed network connections.Conversely, relative to an example high end information processingsystem 104, each neuromodulation system 102 may include less storagecapacity, a single microprocessor, and a single network connection.

It should be appreciated that users as described herein may include anyperson or entity which uses the presently disclosed system and mayinclude a wide variety of parties. For example, the users describedherein may refer to various different entities, including patients,physicians, administrative users, mobile device users, privateindividuals, and/or commercial partners. It should also be appreciatedthat although the user in this specification is often described as apatient, the patient may be instead any of the users described herein.

Neuromodulation system 102 and/or servers 108 may store files, programs,databases, and/or web pages in memories for use by informationprocessing system 104, and/or other information processing systems 104or servers 108.

Neuromodulation system 102 and/or server 108 may be configured accordingto its particular operating system, applications, memory, hardware,etc., and may provide various options for managing the execution of theprograms and applications, as well as various administrative tasks.Information processing system 104 and/or server 108 may interact via atleast one network with at least one other information processing system104 and/or server 108, which may be operated independently. Informationprocessing systems 104 and servers 108 operated by separate and distinctentities may interact together according to some agreed upon protocol.

A detailed block diagram of the electrical systems of an examplecomputing device is illustrated in FIG. 2. The example computing devicemay include any of the devices and systems described herein, includingneuromodulation system 102, information processing system 104 and server108. In this example, the example computing devices may include mainunit 202 which preferably includes at least one processor 204electrically connected by address/data bus 206 to at least one memorydevice 208, other computer circuitry 210, and at least one interfacecircuit 212. Processor 204 may be any suitable processor, such as amicroprocessor from the INTEL® PENTIUM® family of microprocessors.Processor 204 may include one or more microprocessors, centralprocessing units (CPUs), computing devices, microcontrollers, digitalsignal processors, or like devices or any combination thereof. Memory208 preferably includes volatile memory and non-volatile memory.Preferably, memory 208 stores software program(s) that interact with theother devices in system 100 as described below. This program may beexecuted by processor 204 in any suitable manner. In an exampleembodiment, memory 208 may be part of a “cloud” such that cloudcomputing may be utilized by neuromodulation system 102, informationprocessing system 104 and server 108. Memory 208 may also store digitaldata indicative of documents, files, programs, web pages, etc. retrievedfrom computing devices 102, 103 and 104 and/or loaded via input device214.

Interface circuit 212 may be implemented using any suitable interfacestandard, such as an Ethernet interface and/or a Universal Serial Bus(USB) interface. At least one input device 214 may be connected tointerface circuit 212 for entering data and commands into main unit 202.For example, input device 214 may be at least one of a keyboard, mouse,touch screen, track pad, track ball, isopoint, image sensor, characterrecognition, barcode scanner, and a voice recognition system.

As illustrated in FIG. 2, at least one display device 112, printers,speakers, and/or other output devices 216 may also be connected to mainunit 202 via interface circuit 212. Display device 112 may be a cathoderay tube (CRTs), a liquid crystal display (LCD), or any other suitabletype of display device. Display device 112 may be configured to generatevisual displays during operation of neuromodulation system 102,information processing system 102 and/or server 108. A user interfacemay include prompts for human input from user 114 including links,buttons, tabs, checkboxes, thumbnails, text fields, drop down boxes,etc., and may provide various outputs in response to the user inputs,such as text, still images, videos, audio, and animations.

At least one storage device 218 may also be connected to main device orunit 202 via interface circuit 212. At least one storage device 218 mayinclude at least one of a hard drive, CD drive, DVD drive, and otherstorage devices. At least one storage device 218 may store any type ofdata, such content data, statistical data, historical data, databases,programs, files, libraries, pricing data and/or other data, etc., whichmay be used by neuromodulation system 102, information processing system104 and/or server 108.

Neuromodulation system 102, information processing system 104 and/orserver 108 may also exchange data with other network devices 220 via aconnection to network 106. Network devices 220 may include at least oneserver 226, which may be used to store certain types of data, andparticularly large volumes of data which may be stored in at least onedata repository 222. Server 226 may include any kind of data 224including user data, application program data, content data, statisticaldata, historical data, databases, programs, files, libraries, pricingdata and/or other data, etc. Server 226 may store and operate variousapplications relating to receiving, transmitting, processing, andstoring the large volumes of data. It should be appreciated that variousconfigurations of at least one server 226 may be used to support andmaintain system 100. In some example embodiments, server 226 is operatedby various different entities, including private individuals,administrative users and/or commercial partners. Also, certain data maybe stored in neuromodulation system 102, information processing system104 and/or server 108 which is also stored on server 226, eithertemporarily or permanently, for example in memory 208 or storage device218. The network connection may be any type of network connection, suchas an Ethernet connection, digital subscriber line (DSL), telephoneline, coaxial cable, wireless connection, etc.

Access to neuromodulation system 102, information processing system 104and/or server 108 can be controlled by appropriate security software orsecurity measures. A user's access can be defined by neuromodulationsystem 102, information processing system 104 and/or server 108 and belimited to certain data and/or actions. Accordingly, users of system 100may be required to register with neuromodulation system 102, informationprocessing system 104 and/or server 108.

As noted previously, various options for managing data located withinneuromodulation system 102, information processing system 104 and/orserver 108 and/or in server 226 may be implemented. A management systemmay manage security of data and accomplish various tasks such asfacilitating a data backup process. The management system may update,store, and back up data locally and/or remotely. A management system mayremotely store data using any suitable method of data transmission, suchas via the Internet and/or other networks 106.

FIG. 3 is a block diagram showing an example neuromodulation system 300.It should be appreciated that neuromodulation system 300 illustrated inFIG. 3 may be implemented as neuromodulation system 102.

As illustrated in FIG. 3, in this example, neuromodulation system 300may include neuromodulation stimulator device 302 which is operativelyconnected to at least one electrode 308. Neuromodulation stimulatordevice 302 may be connected to at least one electrode 308 in anysuitable way. In one example, neuromodulation stimulator device 302 isdirectly connected to at least one electrode 308. In another example,where at least one electrode 308 is implanted, neuromodulationstimulator device 302 is connected to at least one electrode 308 via awireless connection.

Referring to FIG. 3, in this example, neuromodulation stimulator device302 includes first signal generator 304, second signal generator 306 anddatabase system 310. First signal generator 304, second signal generator306 and database system 310 may include software and/or hardwarecomponents, such as a field programmable gate array (FPGA) or anapplication specific integrated circuit (ASIC), which performs certaintasks. First signal generator 304, second signal generator 306 anddatabase system 310 may advantageously be configured to reside on anaddressable storage medium and configured to be executed on one or moreprocessors. Thus, first signal generator 304, second signal generator306 and database system 310 may include, by way of example, components,such as software components, object-oriented software components, classcomponents and task components, processes, functions, attributes,procedures, subroutines, segments of program code, drivers, firmware,microcode, circuitry, data, databases, data structures, tables, arrays,and variables. The functionality provided for in the components andmodules may be combined into fewer components and modules or furtherseparated into additional components and modules.

Database system 310 may include a wide variety of data. For example,database system may include any of the following data: user data,application program data, content data, statistical data, historicaldata, databases, programs, files, libraries, pricing data and/or otherdata, etc.

In some example embodiments, at least one electrode 308 includes singleor multiple arrays and may be placed on the skin overlying the spinalcord, spinal nerve(s), nerve root(s), ganglia, peripheral nerve(s),brain stem or target areas such as skeletal muscles.

In some embodiments, the at least one electrode is made of a conductinggel or reservoir of water soluble/salt solution. In some embodiments,the implantable electrodes are made of biocompatible material such assilicone and may be embedded with an inert metal such as gold orplatinum wires.

As illustrated in FIG. 4, a flowchart of an example process 400 includesdelivering a generated first signal and a generated second oroverlapping signal. Process 400 may be embodied in one or more softwareprograms which are stored in one or more memories and executed by one ormore processors. Although process 400 is described with reference to theflowchart illustrated in FIG. 4, it should be appreciated that manyother methods of performing the acts associated with process 400 may beused. For example, the order of many of the steps may be changed, someof the steps described may be optional, and additional steps may beincluded.

More specifically, in one example, the neuromodulation system generatesa first signal, as indicated by block 402. For example, first signalgenerator 302 may generate a 40 Hz biphasic signal.

As indicated by block 404, the neuromodulation system generates a secondsignal. For example, second signal generator 304 may generate anoverlapping 10 kHz signal.

As indicated by block 406, the neuromodulation system delivers thegenerated first signal and the generated second signal. For example, theneuromodulation system may transcutaneoulsy deliver, via an electrodepositioned on a spinal cord, the generated 40 Hz biphasic signal withthe overlapping 10 kHz signal.

FIGS. 5A and 5B are diagrammatic views of an example neuromodulationsystem 500, illustrating an example arrangement or placement of aplurality of electrodes. In this example embodiment, neuromodulationsystem 500 includes trancutaneous electrical stimulator 502 which isoperatively connected to at least one electrode or active electrode 504,first ground electrode 506 and second ground electrode 508. As bestshown in FIG. 5B, in this example arrangement, active electrode 504 isdisposed on the user's trunk. Such a configuration enables theneuromodulation system to deliver symmetrical activation.

FIG. 6 is a diagrammatic view of alternative arrangements of differenttypes of electrodes.

An active electrode may be placed in any suitable location. For example,as shown in FIG. 6, an active electrode may be placed overlying theuser's neck, as shown by 602 a, overlying the user's trunk, as shown by602 b, overlying the user's lower back, as shown by 602 c, and/oroverlying the base of a skull (i.e., the brainstem) (not shown).

As illustrated in FIG. 6, superficial electrodes may be positioned in aplurality of different locations. For example, superficial electrodes604 a are positioned overlying muscles of the neck or throat.Superficial electrodes 604 b may be positioned overlying muscles of thediaphragm. Superficial electrodes 604 c may be positioned overlying thekidney region. Superficial electrodes 604 d may be positioned overlyingthe stomach region. Superficial electrode 604 e may be positionedoverlying the pubic region. Superficial electrodes 604 f may bepositioned overlying the shoulder or upper arm. Superficial electrodes604 g may be positioned overlying the biceps or upper arm. Superficialelectrodes 604 h may be positioned overlying the forearm. Superficialelectrodes 604 i may be positioned overlying the upper leg or thigh.Superficial electrodes 604 j may be positioned overlying the lower legor calf Superficial electrodes 604 k may be positioned overlying thelower leg or shin. Superficial electrodes 604 l may be positionedoverlying muscles of the neck or throat.

In one example embodiment, at least one electrode is configured to beimplanted in a user. In this example, system 100 includes an electricalstimulator which wirelessly communicates with the at least one implantedelectrode. In one example embodiment, the transcutaneous electricalstimulator causes the implanted electrode to deliver the generated firstsignal and the generated second signal. In some embodiments, the atleast one implanted electrode is configured to record data andwirelessly transmit the recorded data to the electrical stimulator. Insome embodiments, where the at least one electrode is implanted, the atleast one electrode is configured to deliver the first generated signaland not the second generated signal. That is, in this example, thesecond generated signal is not needed.

In some embodiments, system 100 is configured to wirelessly communicatewith adjunctive or ancillary equipment such as the footwear described inU.S. Pat. No. 7,726,206 which is hereby incorporated by reference in itsentirety. The adjunctive or ancillary equipment may include at least oneof a drug pump, drug delivery systems, physical therapy or skeletalsupport systems.

As discussed above, in some embodiments, the neuromodulation systemgenerates and delivers a first signal and a second signal. FIG. 7illustrates one example of a signal which is delivered by the modulationsystem via at least one electrode. In this example, the signal is a 1-40bipolar rectangular stimulus with a duration between 0.3 and 1.0 ms,filled with a carrier frequency of 5-10 kHz. The signal illustrated inFIG. 7 may result in less skin impedance, and more comfortable andrelatively painless treatment which yields greater compliance and betteroutcomes.

In one example embodiment, the neuromodulation system includes atransistor (e.g., a push-pull transistor) which is configured to set thevoltage of the delivered signal. The signal may be coupled through atransformer to patient channels or electrodes. Using switches, thechannels or electrodes are activated and the signal is applied. Theneuromodulation system may may include an opto-coupler current detectioncircuit. The signal may vary in duration, pulse frequency, pulse trainduration and number of pulse trains.

In one example embodiment, for locomotion, the delivered signal is 30-40Hz at 85-100 mA with an overlapping filling frequency of 10 kHZ.

The generated second or overlapping signal may have a frequency between5 kHz and 10 kHz. In some embodiments, the generated second signal isadjustable between 5 kHz and 10 kHz.

In one example embodiment, the neuromodulation system is configured todeliver a bipolar rectangular stimulus with a pulse duration of 0.5 ms,filled with a carrier frequency of 10 kHz.

In one example embodiment, the neuromodulation system is configured todeliver biphasic stimuli filled with a carrier frequency of 10 kHz. Inthis example, the biphasic stimuli filled with a carrier frequency of 10kHz may suppress the sensitivity of pain receptors of the subject. Inanother example embodiment, the neuromodulation system is configured todeliver biphasic stimuli filled with a carrier frequency of 5-10 kHz.

In some embodiments, the neuromodulation system sums the first generatedsignal and the second generated signal to generate a signal that isdelivered to the electrode. In some embodiments, the neuromodulationsystem includes a frequency mixer configured to add or sum the firstgenerated signal and the second generated signal.

In some embodiments, the neuromodulation system is configured to senddifferent frequencies to two or more different electrodes which may bespatially separated on the surface of a patient's body.

In some embodiments, the neuromodulation system synchronizes the phasingbetween the first generated signal and the second generated signal atone point in time. In some embodiments, where the higher frequency is aninteger multiple of the lower frequency, the neuromodulation systemrepeatedly synchronizes the phasing between the first generated signaland the second generated signal.

In one example embodiment, electrical stimulation is delivered at 1-100Hz and at 30-200 mA.

In one example embodiment, electrical stimulation is delivered at 5-40Hz and at one of 0-300 mA, 1-120 mA, 20-100 mA and 85-100 mA.

In one example embodiment, the frequency of the delivered signal isadjustable. In some embodiments, the frequency of the first generatedsignal is adjustable from 0.0-40 Hz.

In some embodiments, the pulse duration of the delivered signal isadjustable. In some embodiments, the pulse duration of at least one ofthe generated signals is adjustable from 0.5-3.0 ms.

In some embodiments, the amount of amplitude of the delivered signal isadjustable. In some embodiments, the amplitude is adjustable from 0-300mA.

In some embodiments, the stimulation is continuous. In some embodiments,the stimulation is intermittent.

In some embodiments, the system enables ongoing identification of theoptimal stimulation pattern, and allows for adjustment of thestimulating pattern by: (a) auto regulation; (b) direct manual control;or (c) indirect control though wireless technology.

In some embodiments, the neuromodulation system is configured to adjuststimulation and control parameters of the stimulator to levels that aresafe and efficacious using parameters chosen to target specific neuralcomponents, or end organs and customized to each patient based onresponse to evaluation and testing.

In some embodiments, the system targets specific components of thenervous system with a desired predetermined stimulation parameter orseries of stimulation parameters. In one example, in the case oflocomotion, a monopolar electrode is placed over the paravertebralspaces of the thoracic vertebrae of T11-T12, with a reference electrodeplaced over the abdomen; the system is programmed to deliver 5-40 Hzsignal at 85-100 mA with an overlapping high frequency pulse of 10 kHz.

In some embodiments, the neuromodulation system includes at least onesensor. In one example embodiment, the neuromodulation system determinesstimulation parameters based on physiological data collected by the atleast one sensor.

The at least one sensor may include at least one of an Electromyography(“EMG”) sensor, a joint angle (or flex) sensor, an accelerometer, agyroscope sensor, a flow sensor, a pressure sensor, a load sensor, asurface EMG electrode, a foot force plate sensor, an in-shoe sensor, anaccelerator, a motion capture system, and a gyroscope sensor attached toor positioned adjacent the body of the subject.

The stimulation parameters may identify a waveform shape, amplitude,frequency, and relative phasing of one or more electrical pulsesdelivered to one or more pairs of the plurality of electrodes.

The at least one sensor may be connected to the neuromodulation systemin any suitable way. For example, the at least one sensor may beconnected via wires or wirelessly.

In some embodiments, the neuromodulation system includes at least onerecording electrode. The neuromodulation system may be configured toreceive and record electrical signals received from the at least onerecording electrode. The at least one recording electrode may bepositioned on an electrode array. The electrode array may be considereda first electrode array, and the system may include a second electrodearray. The at least one recording electrode may be positioned on atleast one of the first electrode array and the second electrode array.In some embodiments, the neuromodulation system includes a recordingsubsystem which is configured to record signals from the at least onerecording electrode. The recording subsystem may include amplifierswhich may be implemented as low noise amplifiers with programmable gain.

In some embodiments, the neuromodulation system includes a plurality ofmuscle electrodes which cause muscle to move (e.g., contract) to augmentthe improved neurological function provided by the complex stimulationpatterns alone. The neuromodulation system may deliver electricalstimulation to the plurality of muscle electrodes.

In some embodiments, the neuromodulation system includes a stimulatordevice operatively connected to the electrodes. The stimulator devicemay include a casing which is configured to house a signal generator anda control module. The signal generator may be configured to signalgenerate the signals discussed herein. The control module may beconfigured to control the signal generator. The casing may be made ofmolded plastic and may be made compact and portable for single patientuse.

The neuromodulation system may be configured to determine a set ofstimulation parameters by performing a machine learning method based onsignals received from a sensor. In one example, the machine learningmethod implements a Gaussian Process Optimization.

In one example embodiment, the neuromodulation system includes aplurality of electrodes. In this example, the neuromodulation systemdelivers stimulation or generated signals via a selected one or more ofthe electrodes.

In some embodiments, the neuromodulation system may be configured withat least one of the following properties or features: (a) a form factorenabling the neurostimulator device to be worn; (b) a power generatorwith rechargeable battery; (c) a secondary back up battery; (d)electronic and/or mechanical components encapsulated in a package madefrom one or more synthetic polymer materials; (d) programmable andautoregulatory; (e) ability to record field potentials; (f) ability tooperate independently, or in a coordinated manner with other implantedor external devices; and (g) ability to send, store, and receive datavia wireless technology.

In some embodiments, the system is capable of open and closed loopfunctionality, with the ability to generate and record field potentials,evoked potentials and/or modulate membrane potentials of cells andneuronal circuits.

In some embodiments, the stimulator device includes a rechargeablebattery or AC current. In some embodiments, the stimulator deviceincludes a dual power source (e.g., back up battery). In someembodiments, the system includes a power generator with a rechargeablebattery.

In some embodiments, the non-invasive neurostimulator or neuromodulationdevices may be used to deliver therapy to patients to treat a variety ofsymptoms or conditions such as post traumatic pain, chronic pain,neuropathy, neuralgia, epilepsy, spasm, and tremor associated with andwithout Parkinson's disease.

Unless defined otherwise, technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs.

The term “motor complete” when used with respect to a spinal cord injuryindicates that there is no motor function below the lesion, (e.g., nomovement can be voluntarily induced in muscles innervated by spinalsegments below the spinal lesion.

The term “monopolar stimulation” refers to stimulation between a localelectrode and a common distant return electrode.

The term “autonomic function” refers to functions controlled by thenervous system that are controlled largely below the level ofconsciousness, and typically involve visceral functions. Illustrativeautonomic functions include, but are not limited to control of bowel,bladder, and body temperature.

The term “sexual function” refers to the ability to sustain a penileerection, have an orgasm (male or female), generate viable sperm, and/orundergo an observable physiological change associated with sexualarousal.

The term “cognitive function” refers to awareness of one's surroundingenvironment and the ability to function effectively, behaviorally, andmentally in a given environment.

It was discovered that transcutaneous electrical stimulation (tECS) ofthe spinal cord can induce activation locomotor circuitry in a mammal(e.g., in a human or a non-human mammal). It was demonstrated, forexample, that continuous tESCS at 5-40 Hz applied paraspinally overT11-TI2 vertebrae at 40-70 mA induced involuntary locomotor likestepping movements in subjects with their legs in a gravity-independentposition. The increase of frequency of tSCS from 5 to 30 Hz resulted inaugmentation of the amplitude of evoked stepping movements. In chronicspinal cats (3 weeks after spinal cord transection at Th8) tESCS at L5(a frequency of 5 Hz and intensity ranged from 3 to 10 mA) evoked EMGstepping pattern in hindlimb muscles in all (N=4) of tested animals,while locomotor-like movements produced by tESCS were notweight-bearing.

By non-limiting example, transcutaneous electrical stimulation can beapplied to facilitate restoration of locomotion and other neurologicfunction in subjects suffering with spinal cord injury, as well as otherneurological injury and illness. Successful application can provide adevice for widespread use in rehabilitation of neurologic injury anddisease.

The neuromodulation system may facilitate movement in a mammaliansubject (e.g., a human) having a spinal cord injury, brain injury, orother neurological disease or injury. In certain embodiments, theneuromodulation system is configured to stimulate the spinal cord of thesubject using a surface electrode where the stimulation modulates theelectrophysiological properties of selected spinal circuits in thesubject so they can be activated by proprioceptive derived informationand/or input from supraspinal. In some embodiments, stimulation may beaccompanied by physical training (e.g., movement) of the region wherethe sensory-motor circuits of the spinal cord are located.

In some embodiments, the neuromodulation system is configured tostimulate the spinal cord with electrodes that modulate theproprioceptive and supraspinal information which controls the lowerlimbs during standing and/or stepping and/or the upper limbs duringreaching and/or grasping conditions. It is the proprioceptive andcutaneous sensory information that guides the activation of the musclesin a coordinated manner and in a manner that accommodates the externalconditions, e.g., the amount of loading, speed, and direction ofstepping or whether the load is equally dispersed on the two lowerlimbs, indicating a standing event, alternating loading indicatingstepping, or sensing postural adjustments signifying the intent to reachand grasp.

Unlike approaches that involve specific stimulation of motor neurons todirectly induce a movement, the neuromodulation system described hereinenables spinal circuitry to control the movements. More specifically,the neuromodulation system described herein exploits the spinalcircuitry and its ability to interpret proprioceptive information and torespond to that proprioceptive information in a functional way. In someembodiments, this is in contrast to other approaches where the actualmovement is induced/controlled by direct stimulation (e.g., ofparticular motor neurons).

In one example embodiment, a subject is fitted with one or more surfaceelectrodes that afford selective stimulation and control capability toselect sites, mode(s), and intensity of stimulation via electrodesplaced superficially over, for example, the lumbosacral spinal cordand/or cervical spinal cord to facilitate movement of the arms and/orlegs of individuals with a severely debilitating neuromotor disorder.The subject is provided the generator control unit and is fitted with anelectrode(s) and then tested to identify the most effective subjectspecific stimulation paradigms for facilitation of movement (e.g.,stepping and standing and/or arm and/or hand movement). Using thesestimulation paradigms, the subject practices standing and stepping,reaching or grabbing, and/or breathing and speech therapy in aninteractive rehabilitation program while being subject to spinalstimulation.

Depending on the site/type of injury and the locomotor activity it isdesired to facilitate, particular spinal stimulation protocols include,but are not limited to, specific stimulation sites along thelumbosacral, thoracic, and/or cervical spinal cord; specificcombinations of stimulation sites along the lumbosacral, thoracic,and/or cervical spinal cord and/or brainstem; specific stimulationamplitudes; specific stimulation polarities (e.g., monopolar and bipolarstimulation modalities); specific stimulation frequencies; and/orspecific stimulation pulse widths.

In some embodiments, the neuromodulation system is designed so that thepatient can use and control it in the home environment.

In some embodiments, the approach is not to electrically induce awalking pattern or standing pattern of activation, but toenable/facilitate it so that when the subject manipulates their bodyposition, the spinal cord can receive proprioceptive information fromthe legs (or arms) that can be readily recognized by the spinalcircuitry. Then, the spinal cord knows whether to step or to stand or todo nothing. In other words, this enables the subject to begin steppingor to stand or to reach and grasp when they choose after the stimulationpattern has been initiated.

Moreover, the neuromodulation system described herein is effective in aspinal cord injured subject that is clinically classified as motorcomplete; that is, there is no motor function below the lesion. In someembodiments, the specific combination of electrode(s)activated/stimulated and/or the desired stimulation of any one or moreelectrodes and/or the stimulation amplitude (strength) can be varied inreal time, e.g., by the subject. Closed loop control can be embedded inthe process by engaging the spinal circuitry as a source of feedback andfeedforward processing of proprioceptive input and by voluntarilyimposing fine tuning modulation in stimulation parameters based onvisual, and/or kinetic, and/or kinematic input from selected bodysegments.

In some embodiments, the neuromodulation system is designed so that asubject with no voluntary movement capacity can execute effectivestanding and/or stepping and/or reaching and/or grasping. In addition,the approach described herein can play an important role in facilitatingrecovery of individuals with severe although not complete injuries.

In some embodiments, the neuromodulation system may provide some basicpostural, locomotor and reaching and grasping patterns to a user. Insome embodiments, the neuromodulation system may provide a buildingblock for future recovery strategies. Based on certain successes inanimals and some preliminary human studies (see below), it appears thata strategy combining effective transcutaneous stimulation of theappropriate spinal circuits with physical rehabilitation andpharmacological intervention can provide practical therapies forcomplete SCI human patients. Such an approach may be enough to enableweight bearing standing, stepping and/or reaching or grasping. Suchcapability can give SCI patients with complete paralysis or otherneuromotor dysfunctions the ability to participate in exercise, which isknown to be highly beneficial for their physical and mental health. Insome embodiments, the neuromodulation system may enable movement withthe aid of assistive walkers. While far from complete recovery of allmovements, even simple standing and short duration walking wouldincrease these patients' autonomy and quality of life. Theneuromodulation system described herein (e.g., transcutaneous electricalstimulation) paves the way for a direct brain-to-spinal cord interfacethat could enable more lengthy and finer control of movements.

While the neuromodulation system described herein are discussed withreference to complete spinal injury, it will be recognized that they canapply to subjects with partial spinal injury, subjects with braininjuries (e.g., ischemia, traumatic brain injury, stroke, and the like),and/or subjects with neurodegenerative diseases (e.g., Parkinson'sdisease, Alzheimer's disease, Huntington's disease, amyotrophic lateralsclerosis (ALS), primary lateral sclerosis (PLS), cerebral palsy, andthe like).

In some embodiments, the neuromodulation system may be used inconjunction with physical training (e.g., rigorously monitored (robotic)physical training) and optionally in combination with pharmacologicaltechniques. The neuromodulation system enables the spinal cord circuitryto utilize sensory input as well as newly established functionalconnections from the brain to circuits below the spinal lesion as asource of control signals. The approach is thus designed to enable andfacilitate the natural sensory input as well as supraspinal connectionsto the spinal cord in order to control movements, rather than induce thespinal cord to directly induce the movement. That is, theneuromodulation system facilitates and enhances the intrinsic neuralcontrol mechanisms of the spinal cord that exist post-SCI, rather thanreplace or ignore them.

Processing of Sensory Input by the Lumbosacral Spinal Cord: UsingAfferents as a Source of Control

In some embodiments, the neuromodulation exploits spinal control oflocomotor activity. For example, the human spinal cord may receivesensory input associated with a movement such as stepping, and thissensory information can be used to modulate the motor output toaccommodate the appropriate speed of stepping and level of load that isimposed on lower limbs. Moreover, the human lumbosacral spinal cord hascentral-pattern-generation-like properties. Thus, oscillations of thelower limbs can be induced simply by vibrating the vastus lateralismuscle of the lower limb, by transcutaneous stimulation, and bystretching the hip. The neuromodulation system exploits the fact thatthe human spinal cord, in complete or incomplete SCI subjects, canreceive and interpret proprioceptive and somatosensory information thatcan be used to control the patterns of neuromuscular activity among themotor pools necessary to generate particular movements (e.g., standing,stepping, reaching, grasping, and the like). The neuromodulation systemdescribed herein facilitates and adapts the operation of the existingspinal circuitry that generates, for example, cyclic step-like movementsvia a combined approach of transcutaneous stimulation, physicaltraining, and, optionally, pharmacology.

Facilitating Stepping and Standing in Humans Following a ClinicallyComplete Lesion

Locomotion in mammals is attributed to intrinsic oscillating spinalneural networks capable of central pattern generation interacting withsensory information (Edgerton et al., J. American Paraplegia Soc, 14(4)(1991), 150-157; Forssberg, J. Neurophysiol, 42(4): 936-953 (1979);Grillner and Wallen, Annu. Rev. Neurosci., 8: 233-261 (1985); Grillnerand Zangger, Exp Brain Res, 34(2): 241-261 (1979)). These networks playcritical roles in generating the timing of the complex postural andrhythmic motor patterns executed by motor neurons.

As indicated above, the neuromodulation system described herein caninvolve stimulation of one or more regions of the spinal cord incombination with locomotory activities. Spinal stimulation incombination with locomotor activity results in the modulation of theelectrophysiological properties of spinal circuits in the subject sothey are activated by Proprioceptive information derived from the regionof the subject where locomotor activity is to be facilitated. Further,spinal stimulation in combination with pharmacological agents andlocomotor activity results in the modulation of the electrophysiologicalproperties of spinal circuits in the subject so they are activated byproprioceptive information derived from the region of the subject wherelocomotor activity is to be facilitated.

Locomotor activity of the region of interest can be accomplished by anyof a number of methods known, for example, to physical therapists. Byway of illustration, individuals after severe SCI can generate standingand stepping patterns when provided with body weight support on atreadmill and manual assistance. During both stand and step training ofhuman subjects with SCI, the subjects can be placed on a treadmill in anupright position and suspended in a harness at the maximum load at whichknee buckling and trunk collapse can be avoided. Trainers positioned,for example, behind the subject and at each leg assist as needed inmaintaining proper limb kinematics and kinetics appropriate for eachspecific task. During bilateral standing, both legs can be loadedsimultaneously and extension can be the predominant muscular activationpattern, although co-activation of flexors can also occur. Additionally,or alternatively, during stepping the legs are loaded in an alternatingpattern and extensor and flexor activation patterns within each limbalso alternated as the legs moved from stance through swing. Afferentinput related to loading and stepping rate can influence these patterns,and training has been shown to improve these patterns and function inclinically complete SCI subjects.

Transcutaneous Stimulation of the Lumbosacral Spinal Cord

As indicated above, without being bound by a particular theory, it isbelieved that transcutaneous stimulation (e.g., over the throacic spinalcord) in combination with physical training can facilitate recovery ofstepping and standing in human subjects following a complete SCI.

Spinal cord electrical stimulation has been successfully used in humansfor suppression of pain and spasticity (see, e.g., Johnson and Burchiel,Neurosurgery, 55(1): 135-141 (2004); discussion 141-142; Shealy et al.,AnesthAnalg, 46(4): 489-491 (1967); Campos et al., Appl. Neurophysiol.50(1-6): 453-454 (1987); Dimitrijevic and Sherwood, Neurology, 30 (7 Pt2): 19-27 (1980); Barolat Arch. Med. Res., 31(3): 258-262 (2000);Barolat, J. Am. Paraplegia Soc., 11(1): 9-13 (1988); Richardson et al.,Neurosurgery, 5(3): 344-348). Recent efforts to optimize stimulationparameters have led to a number of research studies focusing on thebenefits of transcutaneous spinal cord stimulation. The location of theelectrode and its stimulation parameters are important in defining themotor response. Use of surface electrode(s), as described herein,facilitates selection or alteration of particular stimulation sites aswell as the application of a wide variety of stimulation parameters.

The following non-limiting examples are offered for illustrativepurposes.

Example 1 Transcutaneous Electrical Stimulation of the Spinal Cord: ANoninvasive Tool for the Activation of Stepping Pattern Generators inHumans

A noninvasive method for activating the SN by means of transcutaneouselectrical spinal cord stimulation (tESCS) is demonstrated in thisExample. The method is based on our research that showed that a singledermal electric stimulus applied in the region of the T11-T12 vertebraecaused monosynaptic reflexes in the proximal and distal leg muscles inhealthy subjects (see Courtine, G., Harkema S. J, Dy, C. J.,Gerasimenko, Yu. P., and Dyhre-Poulsen, P., Modulation of MultisegmentalMonosynaptic Responses in a Variety of Leg Muscles during Walking andRunning in Humans, J Physiology, 2007, vol. 585, p. 1125) and inpatients with clinically complete (ASIA A) spinal cord injury. See Dy,C. J., Gerasimenko, Y P., Edgerton, V R., DyhrePoulsen P., Courtine G.,Harkema S., Phase-Dependent Modulation of Percutaneously ElicitedMultisegmental Muscle Responses after Spinal Cord Injury, JNeurophysiol., 2010, vol. 103, p. 2808. Taking into consideration thateESCS affects the SN through mono and polysynaptic reflexes (seeMinassian, Persy, Rattay, Pinter, Kern, and Dimitrijevic, supra), wesuggest that noninvasive tESCS can be an effective way to neuromodulatethe SN.

Experiment

We examined six healthy adult male subjects (students and staff of theVelikie Luki State Academy of Physical Education and Sports). They hadgiven their informed written consent to participate in the experiment.The experiment was approved by the Ethics Committee of the academy andmet the requirements of the Helsinki Declaration.

The subjects lay on a couch on their left side, with their feet placedon separate boards that were attached to a hook in the ceiling of theexperimental room with ropes, like swings. The right (upper) leg wassupported directly in the region of the shank. The left (lower) leg wasplaced in a rotating frame attached to a horizontal board. Under theseconditions, the subjects could move their legs through maximumamplitude: According to the instructions, the subjects lay quietly andneither counteracted nor facilitated the movements caused by electricalstimulation of the spinal cord.

The tESCS was performed using a KULON stimulator (St. Petersburg StateUniversity of Aerospace Instrumentation, St. Petersburg, Russia). Thestimulation was administered using a 2.5 cm round electrode (Lead-Lok,Sandpoint, United States) placed midline on the skin between the spinousprocesses of T11 and T12 as a cathode and two 5.0×10.2 cm rectangularplates made of conductive plastic (Ambu, Ballerup, Germany) placedsymmetrically on the skin over the iliac crests as anodes. The step-likemovements were evoked by a bipolar rectangular stimulus with a durationof 0.5 ms, filled with a carrier frequency of 10 kHz; the intensity ofstimulation ranged from 30 to 100 mA. The stimulation frequencies were1, 5, 10, 20, 30, and 40 Hz; the duration of exposure ranged from 10 to30 s. During the high-frequency stimulation within each stimulus, tESCSdid not cause pain even when the amplitude was increased to 100 mA ormore; allowing us to study in detail the dependence of the elicitedmovements on the amplitude and frequency of the stimulus.

The EMGs of the muscles of both legs (m. rectus femoris, m. bicepsfemoris, m. tibialis anterior, and m. gastrocnemius) were recorded bymeans of bipolar surface electrodes. EMG signals were recorded using anME 6000 16-channel telemetric electroneuromyograph (Mega Win, Finland).Flexion-extension movements in the knee joints were recorded using agoniometer.

The Qualisy video system (Sweden) was used to record the kinematicparameters of leg movements. Light-reflecting markers were attached tothe pivot points of the body, which coincided with the rotational axisin the shoulder, hip, knee, and ankle joints. The angular movements inthe hip joint were calculated from the location of markers on thelateral epicondyle of the humerus, trochanter, and lateral epicondyle ofthe femur. The markers that were attached to the trochanter, lateralepicondyle of the femur, and lateral ankle were used to describe themovements in the knee joint. The movements in the ankle joint wereestimated by means of the markers located on the lateral epicondyle ofthe femur, lateral ankle, and the big toe. The reconstruction ofmovements in one whole step cycle was performed by means of a specialsoftware. In order to record the movements of the foot tip, the markerwas fixed on the big toe of the right foot.

The recording of EMG was synchronized with the recording of steppingkinematical parameters. The average cycle duration and the amplitudes ofangular movements were calculated from 10-12 cycles. The duration of astep cycle was calculated on the basis of the interval between twomaximum values of angular movements in the hip, knee, and ankle joints.The phase shift between the hip and knee joints was calculated from theinterval between the maximum values of angular movements in thesejoints.

The statistical treatment of the data was performed using a standardsoftware package.

Results

Transcutaneous electrical spinal cord stimulation with a frequency of5-40 Hz elicited involuntary leg movements in five out of six subjects.The threshold intensity of the stimulus that induced involuntarymovements was 50-60 mA and was dependent on the frequency ofstimulation. The tESCS at a frequency of 1 Hz caused reflex responses inthe leg muscles with a threshold of 70-80 mA (FIG. 8a ).

Original records of EMG responses in the muscles of the right leg to thetESCS at a frequency of 1 Hz and intensity of 75-100 mA are shown inFIG. 8. Increasing stimulus intensity resulted in an increase in theamplitude of responses. First, the hip muscles (m. rectus femoris and m.biceps femoris) were involved in the motor response; then, the shankmuscles (m. tibialis anterior and m. gastrocnemius) were involved (FIG.8b ). The response to each stimulus is composed of the earlymonosynaptic responses (the same is shown in Courtine, Harkema, Dy,Gerasimenko, and Dyhre-Poulsen, supra) with a latency period of about12-15 ms. Increasing stimulus intensity evoked responses in the bicepsfemoris muscle (flexor) with a latent period of a few tens ofmilliseconds, which were, apparently, polysynaptic. Thus, tESCS with alow frequency (1 Hz) elicited reflex responses in the leg muscles thatcontained mono and polysynaptic components.

Transcutaneous electrical spinal cord stimulation at frequencies in theentire range from 5 to 40 Hz caused step-like movements in five subjects(FIG. 9). There was some variability in the ability of tESCS to evokestep-like movements at different frequencies of stimulation. In twosubjects (R. and S.), step-like movements were evoked by tESCS at allthe test frequencies in the range 5-40 Hz; in subjects K and G., theywere recorded at frequencies of 5, 10, 20, and 30 Hz; and in subject B,they were recorded at frequencies of 5 and 30 Hz. The latent period ofthe starting of movements did not depend on the frequency of stimulationand was in the range of 0.2-2.5 s. The amplitude of movements insubjects S, G, and R at the beginning of stimulation gradually increasedto the maximum, and after its termination it gradually decreased. Insubjects K and V, the movements terminated against the background ofongoing tESCS, the duration of the stepping pattern was approximately10-20 s. In subjects R and S, the movements continued during the wholeperiod of stimulation and ended 2-4 s after its termination.

Pair wise comparison of the mean amplitudes of the movements of the hip,knee, and ankle joints calculated during the first and the last 15 s ofstimulation at each of the frequencies used allowed us to determine theprobability of the differences in the amplitudes of the inducedmovements at the beginning and at the end of the stimulation (see Table1, below). Two rows of probabilities for subject C, calculated on thebases of two experiments show the different direction of the changes inthe amplitudes at the beginning and end of stimulation. In the table,the cases when the amplitude of movements at the end of the stimulationwas significantly greater than in the beginning are boldfaced; the caseswhen the amplitude of movements at the end of the stimulation wassignificantly lower than in the beginning are italicized. According tothe data, the subjects were divided into two groups. In the first group(subjects R and S), step-like movements were evoked by the stimulationat the entire range of the frequencies studied (5-40 Hz), and theamplitude of movements, while growing at the beginning of stimulation,decayed after its termination. In the second group (subjects K and V),the movements were evoked with difficulty and with a limited set offrequencies. These differences could be related both to the individualcharacteristics of the electrical conductivity of the skin and tocharacteristics of the spinal connections.

The involuntary movements of the legs caused by tESCS fully compliedwith the characteristics of stepping movements (FIG. 10). Like voluntarystepping movements, the involuntary movements caused by tESCS surelycontain the alternating contractions of the similar muscles of the leftand right legs and the alternation of antagonist muscle activity in thehip and shin (rectus femoris and biceps femoris, gastrocnemius andtibial muscle of the shin). As clearly seen in the curves reflecting themotion of the hip and knee joints, the movements in these joints, bothvoluntary and evoked by tESCS, occurred with a phase shift (the motionin the knee ahead of the motion in the hip).

The table below shows the probability of similarity of the meanamplitudes of movements, measured in the first and the last 15 s duringtESCS. For subject S., two different cases of stimulation are shown.

TABLE 1 The Frequency of Stimulation Subject Joint 5 Hz 10 Hz 20 Hz 30Hz 40 Hz S. (1) H 0.08 0.16 0.20 0.005 0.1 Kn 0.003 0.26 0.41 0.030.0003 Ank 0.08 0.07 0.18 0.20 0.07 S. (2) H 0.01 0.0001 0.004 0.82 0.92Kn 0.04 0.0001 0.002 0.0004 0.12 Ank 0.002 0.0006 0.002 0.001 0.08 R. H0.07 0.05 0.14 0.27 0.007 Kn 0.0001 0.001 0.03 0.01 0.15 Ank 0.02 0.0080.003 0.47 0.68 K. H 0.99 0.002 Kn 0.03 0.008 Ank 0.21 0.001 B. H 0.030.16 0.27 0.68 Kn 0.12 0.06 0.04 0.02 Ank 0.05 0.99 0.15 0.001 G. H0.004 0.16 0.21 0.16 Kn 0.05 0.08 0.24 0.26 Ank 0.005 0.05 0.29 0.009Notes: H, hip joint; Kn, knee joint; Ank, ankle joint. The cases where p≦ 0.05 are boldfaced and italicized. Other explanations are in the text.

Stepping cycles in three joints of the right leg during voluntarystepping movements (FIG. 11a ) and movements elicited by tESCSreconstructed based on the kinematic analysis and the trajectory of thetip of the foot (the big toe) are shown in FIG. 11. In step-likemovements elicited by tESCS, as in voluntary stepping movements, thephase of carrying the leg forward and the phase of support during thebackward leg movements were distinct (FIGS. 11a, 11b ). During voluntarymovements, the patterns of the knee and ankle joints are more complexthan during the elicited movements. The coordination between the jointsduring the evoked movements is very different from that observed duringvoluntary movements (FIGS. 11c, 4d ). The same is true for the movementsof the distal region of the leg, resulting from the interaction ofmovements in all three joints, and recorded using a marker attached tothe big toe (FIG. 11f ). The trajectory of the terminal point involuntary movements looked like an ellipse (FIG. 11f ). The trajectoryof the terminal point in the movements elicited by tESCS may beconsidered a confluent ellipse, with the leg moving forward and backwardwithout significant vertical movements.

The frequency of step-like movements did not depend on the frequency ofstimulation. The average periods of step-like movements in subjects R,S, K, B, and G were 2.72±0.14, 2.39±0.55, 2.42±0.15, 3.22±0.85, and1.9±0.09 s, respectively.

As mentioned above, the pair wise comparison of the mean amplitudes ofthe movements in the hip, knee, and ankle joints calculated in the firstand the last 15 s of stimulation in different subjects, showed that,regardless of the stimulation frequency, the amplitude of movements mayeither increase or decrease significantly. At the beginning ofstimulation, there was a tendency for the amplitude of movements toincrease with increasing frequency of stimulation in all subjects forall joints (FIG. 12). However, at the end of stimulation, the amplitudeof movements was independent of the stimulation frequency. In alljoints, minimum movements were observed at a stimulation frequency of 5Hz (FIGS. 12b, 12d ). As an exception, only in one case, when subject S.was stimulated, the amplitude of movements in the hip joint increasedwith increasing stimulation frequency and the amplitude of movements inthe knee and ankle joints decreased with increasing frequency [FIG. 12;table 1, subject S. (1)]. The trajectory of movement of the big toe ofthis subject, reflecting the amplitude of the whole leg's movement, isshown in FIG. 12a . In this case, the amplitude of movement of the tipof the foot at stimulation frequencies of 10, 20, 30, and 40 Hz was,respectively, 15.0, 19.9, 15.3, and 16.4 times greater than at 5 Hz. Inthe case shown in FIG. 12b , it was, respectively, 3.5, 9.4, 11.3, and80.7 times greater than at 5 Hz. Thus, in this subject, with increasingfrequency of stimulation, the amplitude of leg movements did notdecrease in any of the cases; it was minimal at a frequency of 5 Hz.

Note that, in the cases shown in FIGS. 12b and 12d , an increase infrequency resulted in a significant increase in the amplitude ofmovements in the ankle joint. The possibility to control the movementsin the ankle joint via the frequency of stimulation was an advantage oftECS, unlike the ankle joint which was not modulated invibration-induced step-like movements. See Gorodnichev, Machueva,Pivovarova, Semenov, Ivanov, Savokhin, Edgerton, and Gerasimenko, supra.

Discussion

Transcutaneous electrical stimulation of the lumbar enlargement maystrengthen the patterns of EMG activity in leg muscles in patients withcomplete or partial spinal cord lesions during assisted walkingmovements on a moving treadmill. See Minassian, Persy, Rattay, Pinter,Kern, and Dimitrijevic, supra. However, voluntary step-like movementswere never successfully evoked by means of transcutaneous stimulation inthis category of patients before. It was observed that transcutaneouselectrical stimulation applied to the rostral segments of the lumbarenlargement (in the region of the T11-T12 vertebrae) elicitedinvoluntary step-like movements in healthy subjects with their legssuspended in a gravity-neutral position. This phenomenon was observed infive out of the six subjects studied. tESCS did not cause discomfort andwas easily tolerated by subjects when biphasic stimuli filled with acarrier frequency of 10 kHz which suppressed the sensitivity of painreceptors were used.

The Proof of the Reflex Nature of the Responses Evoked by tESCS

A single transcutaneous electrical stimulation in the region of theT11-T12 vertebrae causes responses in leg muscles with a latency periodcorresponding to monosynaptic reflexes. See Courtine, Harkema, Dy,Gerasimenko, and Dyhre-Poulsen, supra. It is assumed that theseresponses are due to the activation of large-diameter dorsal rootafferents. See Minassian, Persy, Rattay, Pinter, Kern, and Dimitrijevic,supra; Dy, C. J., Gerasimenko, Y P., Edgerton, V R., DyhrePoulsen P.,Courtine G., Harkema S., Phase-Dependent Modulation of PercutaneouslyElicited Multisegmental Muscle Responses after Spinal Cord Injury, JNeurophysiol., 2010, vol. 103, p. 2808; de Noordhout, A., Rothwell, J.e., Thompson, P. D., Day, B. L., and Marsden, e. D., PercutaneousElectrical Stimulation of Lumbosacral Roots in Man, J Neurol. Neurosurg.Psychiatry, 1988, vol. 51, p. 174; Troni, W., Bianco, e., Moja, M. C.,and Dotta, M., Improved Methodology for Lumbosacral Nerve RootStimulation, Afuscle Nerve, 1996, vol. 19, no. Iss. 5, p. 595;Dyhre-Poulsen, P., Dy, e.1., Courtine, G., Harkema, S., and Gerasimenko,YU. P., Modulation of Multi segmental Monosynaptic Reflexes Recordedfrom Leg Muscles During Walking and Running in Human Subjects, GaitPosture, 2005, vol. 21, p. 66. The monosynaptic nature of theseresponses is confirmed by the fact that vibration of muscle tendons orpaired stimulation suppresses the responses. We have previously shownthat the responses to the second stimulus were suppressed in rats duringepidural stimulation (see Gerasimenko, Lavrov, Courtine, Ronaldo,Ichiyama, Dy, Zhong, Roy, and Edgerton, supra) and in healthy humans(see Courtine, Harkema, Dy, Gerasimenko, and Dyhre-Poulsen, supra; Dy,Gerasimenko, Edgerton, Dyhre-Poulsen, Courtine, Harkema, supra) duringpaired tESCS with a delay between the stimuli of 50 ms. This refractoryperiod excludes the possibility of direct activation of the motorneurons in the ventral horn or ventral root activation. See Struijk,1.1., Holsheimer, 1., and Boom, H. B. K., Excitation of Dorsal RootFibers in Spinal Cord Stimulation: A Theoretical Study, IEEE Trans.Biorned. Eng., 1993, vol. 40, no. 7, p. 632. The monosynaptic nature ofthe responses was also shown during vibration tests. It is well knownthat vibration suppresses monosynaptic reflex pathways in homologousmuscles. See Mao, e. e., Ashby, P., Wang, M., and McCrea, D., SynapticConnections from Large Muscle Afferents to the Motoneurons of VariousLeg Muscles in Man, Exp. Brain Res., 1984, vol. 56, p. 341. Thesuppression of responses caused by tESCS in shin muscles during thevibration of the Achilles tendon directly shows the monosynaptic natureof these responses. The similarity of modulations of the classicalmonosynaptic H-reflex and reflex responses caused by tESCS duringwalking in healthy subjects (see Courtine, Harkema, Dy, Gerasimenko, andDyhre-Poulsen, supra) and in patients with spinal cord injuries (see Dy,Gerasimenko, Edgerton, Dyhre-Poulsen, Courtine, Harkema, supra) alsosupports the monosynaptic nature of the responses to transcutaneousstimulation. In both cases, the amplitude of modulation of the reflexeswas proportional and phase-dependent on the activation level of eachmuscle. All of the above data indicate the identity of the H-reflex andreflex responses induced by tESCS.

In the flexor muscles affected by tESCS, polysynaptic reflexes weresometimes recorded in addition to the monosynaptic component (FIG. 8).Earlier, we recorded polysynaptic reflexes in the flexor the intact andspinal animals during the single epidural stimulation. See Gerasimenko,Lavrov, Courtine, Ronaldo, Ichiyama, Dy, Zhong, Roy, and Edgerton,supra; Lavrov, 1., Gerasimenko, YU. P., Ichiyama, R., Courtine G., ZhongH., Roy R., and Edgerton R. V, Plasticity of Spinal Cord Reflexes aftera Complete Transection in Adult Rats: Relationship to Stepping Ability,J Neurophysiol., 2006, vol. 96, no. 4, p. 1699. All the above datasuggest that tESCS can activate mono and polysynaptic neuronal networks.

The Characteristics of Transcutaneous Stimulation Eliciting Step-likeMovements

The previous experiments showed that the rostral segments of the lumbarspinal cord may play the role of triggers in initiating locomotormovements. See Deliagina, T. G., Orlovsky, G. N., and Pavlova, G. A.,The Capacity for Generation of Rhythmic Oscillations Is Distributed inthe Lumbosacral Spinal Cord of the Cat, Exp. Brain Res., 1983, vol. 53,p. 81. In spinal patients (see Dimitrijevic, M. R, Gerasimenko, Yu., andPinter, M. M., Evidence for a Spinal Central Pattern Generator inHumans, Ann. N. Y. Acad. Sci., 1998, vol. 860, p. 360) and in spinalrats (Ichiyama, R. M., Gerasimenko, YU. P., Zhong, H., Roy, R. R., andEdgerton V R., Hindlimb Stepping Movements in Complete Spinal RatsInduced by Epidural Spinal Cord Stimulation, New•osci. Lett., 2005, vol.383, p. 339), step-like patterns of EMG activity were evoked by epiduralstimulation of the L2 segment. In our experiments, we usedtranscutaneous electrical stimulation in the region of T11-T12vertebrae, which corresponds to the cutaneous projection of the L2-L3segments of the spinal cord. It was previously shown that theelectromagnetic stimulation of this region in healthy subjects withtheir legs supported externally can initiate walking movements. SeeGerasimenko, Gorodnichev, Machueva, Pivovarova, Semenov, Savochin, Roy,and Edgerton, supra; Gorodnichev, Machueva, Pivovarova, Semenov, Ivanov,Savokhin, Edgerton, and Gerasimenko, supra. These data are consistentwith the current concept on the structural and functional organizationof the SN with distributed pacemaking and pattern-generating systems(see McCrea, D. A. and Rybak, L A., Organization of Mammalian LocomotorRhythm and Pattern Generation, Brain Res. Rev., 2008, vol. 57, no. 1, p.134), in which the rostral lumbar segments of the spinal cord play therole of a trigger of the locomotor function.

The frequency of stimulation is an important characteristic of the motoroutput. It was shown that step-like movements are evoked by stimulationfrequencies in the range of 5-40 Hz. The amplitude of step-likemovements induced by high-frequency stimulation (30-40 Hz) was usuallyhigher than that of the movements induced by low frequency stimulation(5 Hz), although the duration of the stepping cycle varied slightly. Thefact that a wide range of frequencies can effectively induce step-likemovements is probably due to the functional state of the intact spinalcord and its pathways. For example, in spinal patients, the effectivefrequency range for the initiation of step-like movements using epiduralstimulation was 30-40 Hz (according to Dimitrijevic, Gerasimenko, andPinter, supra); in decerebrated cats, the frequency of 5 Hz was the mosteffective to elicit locomotion (according to our data) (see Gerasimenko,Roy, and Edgerton, supra).

The intensity of transcutaneous electrical stimulation (50-80 mA) thatcauses step-like movements is approximately 10 times higher than theintensity of the epidural stimulation initiating walking movements inspinal patients. See Dimitrijevic, Gerasimenko, and Pinter, supra. If weassume that the dorsal roots are the main target for both types ofstimulation, we should agree that the current should be strong toactivate them by transcutaneous electrical stimulation. Thus, weconclude that the location, frequency, and intensity of stimulation arethe factors that determine the activation of the SN by tESCS.

The Origin of the Stepping Rhythm Evoked by tESCS

In most subjects, the involuntary step-like movements in the hip andknee joints were initiated by tESCS with a delay of 2-3 s after thestart of stimulation. Typically, the amplitude of movements in the hipand knee joints increased smoothly and gradually with the subsequentinvolvement of the ankle joint (FIG. 9). A similar character of theinitiation of involuntary step-like movements with gradual involvementof different motor pools of the leg muscles was also observed during thevibration of muscles (see Gurfinkel', Levik, Kazennikov, and Selionov,supra; Selionov, Ivanenko, Solopova, and Gurfinkel', supra; Gorodnichev,Machueva, Pivovarova, Semenov, Ivanov, Savokhin, Edgerton, andGerasimenko, supra) and the epidural spinal cord stimulation. SeeDimitrijevic, Gerasimenko, and Pinter, supra; Minassian, Persy, Rattay,Pinter, Kern, and Dimitrijevic, supra. This suggests that transcutaneouselectrical stimulation, as well as the epidural stimulation, affects theSN through the activation of the dorsal root afferents entering thespinal cord. In addition to the dorsal roots and dorsal columns, thedirect stimulation of the spinal cord may also activate the pyramidaland reticulospinal tracts, ventral roots, motor neurons, dorsal horn,and sympathetic tracts. See Barolat, G., Current Status of EpiduralSpinal Cord Stimulation, Neurosurg. Quart., 1995, vol. 5, no. 2, p. 98;Barolat, G., Epidural Spinal Cord Stimulation: Anatomical and ElectricalProperties of the Intraspinal Structures Relevant To Spinal CordStimulation and Clinical Correlations, Neuromodul. Techn. Neur. Intelf-,1998, vol. 1, no. 2, p. 63. During the tESCS, the electric currentspreads perpendicular to the spinal column with a high density under theparavertebral electrode. See Troni, Bianco, Moja, and Dotta, supra. Thisstimulation apparently activates the dorsal roots immersed in thecerebrospinal fluid, but not the spinal cord neurons, which have a muchlower conductivity. See Holsheimer, J., Computer Modeling of Spinal CordStimulation and Its Contribution to Therapeutic Efficacy, Spinal Cord,1998, vol. 36, no. 8, p. 531. We assume that tESCS consequently involvesin activity the afferents of groups Ia and Ib with the largest diameterand, thus, the lowest threshold, then the afferents of the group II, andthe spinal interneurons mediating polysynaptic reflexes. The presence ofpolysynaptic components in the evoked potentials in the flexor muscles(FIG. 8) confirms that they participate in the SPG. Thus, we can saythat tESCS activates different spinal neuronal systems; however, thedorsal roots with their mono and polysynaptic projections to the motornuclei are the main ones among them. The contribution of mono andpolysynaptic components in the formation of the stepping rhythm causedby tESCS is not known.

In our studies, single pulse stimulation resulted in monosynapticreflexes in the majority of the leg muscles investigated. However, theelectromyographic trains evoked by continuous tESCS that inducedinvoluntary step-like movements were not formed by the amplitudemodulation of monosynaptic reflexes, as it was in spinal rats and duringthe spinal epidural stimulation of patients. See Gerasimenko, Roy, andEdgerton, supra. Our data showed that the activity withinelectromyographic trains was not stimulus-dependent; i.e., EMG trainsdid not consist of separate reflex responses. Similarstimulus-independent EMG trains were observed during involuntarymovements caused by spinal cord electromagnetic stimulation. SeeGerasimenko, Gorodnichev, Machueva, Pivovarova, Semenov, Savochin, Roy,and Edgerton, supra; Gorodnichev, Machueva, Pivovarova, Semenov, Ivanov,Savokhin, Edgerton, and Gerasimenko, supra. In contrast, the step-likemovements evoked by the epidural spinal stimulation in rats and spinalpatients were stimulus-dependent. See Gerasimenko, Roy, and Edgerton,supra. In the extensor muscles, the EMG trains consisted mainly ofmonosynaptic reflexes; in the flexor muscles, polysynaptic reflexesdominated in the EMG trains. See Gerasimenko, Y. P., Ichiyama, R. M.,Lavrov, L A., Courtine, G. Cai, L., Zhong, H., Roy, R. R., and Edgerton,V. R., Epidural Spinal Cord Stimulation Plus Quipazine AdministrationEnable Stepping in Complete Spinal Adult Rats, J Neurophysiol., 2007,vol. 98, p. 2525; Minassian, K., Jilge, B., Rattay, F., Pinter, M. M.,Binder, H., Gerstenbrand, F., and Dimitrijevic, M. R., Stepping-LikeMovements in Humans with Complete Spinal Cord Injury Induced by EpiduralStimulation of the Lumbar Cord: Electromyographic Study of CompoundMuscle Action Potentials, Spinal Cord 2004, vol. 42, p. 401. It is notclear why single cutaneous and, respectively, single epidural spinalcord stimulation causes the same monosynaptic reflexes in healthysubjects and spinal patients; however, continuous stimulation elicitstheir step-like movements through different mechanisms. We assume that,in healthy subjects, tESCS increases the excitability of the neuronallocomotor network, being a trigger for its activation, in the same wayas in the case of vibration-induced step-like movements. See Selionov,Ivanenko, Solopova, and Gurfinkel', supra. However, we need additionalstudies to understand in detail how the tESCS elicits involuntarystep-like movements.

In this study, a new noninvasive access to locomotor spinal neuralnetworks in humans by means of tESCS has been described. A specialdesign of the stimulator, which generated bipolar pulses filled withhigh-frequency carrier, allowed us to stimulate the spinal cordrelatively painlessly and elicit involuntary step-like movements. Thefundamental importance of our study consists in the new data in favor ofthe existence of SN in humans that can coordinate stepping patterns andthe evidence of the possibility to engage this SN using noninvasiveeffects on the structures of the spinal cord. This increases prospectsfor widespread use of transcutaneous techniques in electrical spinalcord stimulation to study the mechanisms underlying the regulation ofthe locomotor behavior in healthy subjects and for the rehabilitationand motor recovery of patients after spinal cord injuries and afterother neuromotor dysfunctions.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

The invention is claimed as follows:
 1. A neuromodulation system forinducing locomotor activity in a mammal, the neuromodulation systemcomprising: a processor; a first signal generator; a second signalgenerator; an electrode; and a memory device storing instructions whichwhen executed by the processor, causes the processor, in cooperationwith the first signal generator, the second signal generator, and theelectrode, to deliver a continuous therapeutic signal at 0.5 Hz to 100Hz with an overlapping high frequency pulse at 5 kHz to 10 kHz to themammal, wherein the processor is configured to synchronize phasingbetween the continuous therapeutic signal and the overlapping highfrequency pulse, wherein the overlapping high frequency pulse isconfigured to suppress sensitivity of pain receptors; and wherein thesignal is delivered at 30-200 mA.
 2. The neuromodulation system of claim1, wherein the mammal is a human.
 3. The neuromodulation system of claim1, wherein the signal is delivered at 85-100 mA.
 4. The neuromodulationsystem of claim 1, wherein the overlapping high frequency pulse is a 10kHz pulse.
 5. The neuromodulation system of claim 1, wherein theoverlapping high frequency pulse is a 5 kHz pulse.
 6. Theneuromodulation system of claim 1, wherein the delivered signal isapplied paraspinally over a neck of the mammal.
 7. The neuromodulationsystem of claim 6, wherein the neck of the mammal includes a cervicalportion of a spinal cord and a brainstem.
 8. The neuromodulation systemof claim 1, wherein the delivered signal is applied paraspinally over alower back of the mammal.
 9. The neuromodulation system of claim 8,wherein the lower back includes at least one of a lumbar portion, alumbosacral portion and a sacral portion of the spinal cord.
 10. Theneuromodulation system of claim 1, wherein the delivered signal isapplied to a thoracic portion of a spinal cord or to an end organ. 11.The neuromodulation system of claim 10, wherein the thoracic portion ofthe spinal cord includes T11-T12 vertebrae.
 12. The neuromodulationsystem of claim 1, wherein the mammal has a spinal cord injury which isclassified as one of motor complete and motor incomplete.
 13. Theneuromodulation system of claim 1, wherein the mammal has an ischemicbrain injury which is an injury from at least one of a stroke and acutetrauma.
 14. The neuromodulation system of claim 1, wherein the mammalhas a neurodegenerative brain injury.
 15. The neuromodulation system ofclaim 14, wherein the neurodegenerative brain injury is a brain injuryassociated with a condition selected from the group consisting ofParkinson's disease, Huntington's disease, Alzhiemers, ischemia, stroke,amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS) orother neurological disorders such as cerebral palsey.
 16. Theneuromodulation system of claim 1, wherein the neuromodulatoin system isused to treat chronic pain, spasm, autonomic function, sexual function,vasomotor function, or cognitive function.
 17. The neuromodulationsystem of claim 1, wherein the system induces motor activity whichcomprises at least one of standing, stepping, a walking motor pattern,sitting down, laying down, reaching, grasping, pulling, chewing,swallowing, sexual function, respiratory function, and pushing.
 18. Theneuromodulation system of claim 1, wherein the therapeutic signal andoverlapping high frequency pulse are square waves and wherein thetherapeutic signal and overlapping high frequency pulse are unequalvalues.
 19. A neuromodulation system comprising: a processor; a firstsignal generator; a second signal generator; an electrode operativelyconnected to the processor; and a memory device storing instructions,which when executed by the processor, causes the processor, incooperation with the first signal generator, the second signalgenerator, and the electrode, to deliver a secondary high frequencyelectric pulse of 10 KHz which overlaps with a continuous therapeuticprimary biphasic low frequency pulse delivered at 0.5 Hz to 100 Hzresulting in less skin impedance and pain free stimulation, wherein thesignal is delivered at 30-200 mA; wherein the processor is configured tosynchronize phasing between the secondary high frequency electric pulseand continuous therapeutic primary biphasic low frequency pulse; andwherein the secondary high frequency electric pulse is configured tosuppress sensitivity of pain receptors.
 20. The neuromodulation systemof claim 19, wherein the primary biphasic low frequency pulse isdelivered at 5-40 Hz.
 21. The neuromodulation system of claim 19,wherein the delivered secondary high frequency electric pulse is appliedparaspinally.